Mitochondrial diseases are a group of disorders caused by dysfunctional mitochondria, the organelles that are the “powerhouses” in cells. Mitochondria are found in every cell of the body except red blood cells. Mitochondria convert the energy of food molecules into the ATP that powers most cell functions. Mitochondrial diseases are often caused by genetics or mutations to the mitochondrial DNA that affect mitochondria function. Mitochondrial diseases take on unique characteristics both because of the way the diseases are often inherited and because mitochondria are so critical to cell function. Mitochondrial diseases elicit in a variety of organs, and with a variety of symptoms, some of which are directly caused by the dysfunction, and others which are the downstream consequences of the dysfunction. For example, the subclass of these diseases that have neuromuscular disease symptoms are often called a mitochondrial myopathy. There is evidence that mitochondrial dysfunction may be a molecular basis of bipolar disorder. In addition, classical mitochondrial diseases occur in a subset of individuals with autism and may be caused by genetic anomalies or mitochondrial respiratory pathway deficits.
The clinical presentation of the mitochondrial disease include poor growth, loss of muscle coordination, muscle weakness, visual problems, hearing problems, learning disabilities, heart disease, liver disease, kidney disease, gastrointestinal disorders, respiratory disorders, neurological problems, autonomic dysfunction, and dementia.
Illustrative mitochondrial diseases and myopathies include Leber's hereditary optic neuropathy (LHON). LHON results in visual loss beginning in young adulthood, eye disorder characterized by progressive loss of central vision due to degeneration of the optic nerves and retina, Wolff-Parkinson-White syndrome, a manifestation of LHON showing as a cardiac condition and/or arrhythmia that is believed herein to be caused by a dysfunctional circuit in the heart conduction. LHON reportedly affects 1 in 50,000 people in Finland.
Illustrative mitochondrial diseases and myopathies include diabetes mellitus and deafness (DAD). DAD is a combination of symptoms that appears at an early age and is believed herein to be caused at least in part by mitochondrial disease. Without being bound by theory, it is believed herein that DAD is a specific manifestation of symptoms resulting from mitochondrial starving of the pancreas, which then leads to a diabetic condition, and accompanying deafness. DAD is not believed herein to be a an autoimmune disease, but rather a particular combination of symptoms that arise from mitochondrial dysfunction.
Illustrative mitochondrial diseases and myopathies include Leigh's disease or Leigh syndrome, a subacute sclerosing encephalopathy. Leigh's disease elicits after normal development, then the disease usually begins late in the first year of life, although onset may occur in adulthood. A rapid decline in function occurs and is marked by seizures, altered states of consciousness, dementia, and ventilatory failure.
Illustrative mitochondrial diseases and myopathies include neuropathy, ataxia, retinitis pigmentosa, and ptosis (NARP). NARP is a disease identified as the progressive set of symptoms represented by the acronym, and may also include dementia.
Illustrative mitochondrial diseases and myopathies include Myoneurogenic gastrointestinal encephalopathy (MNGIE). MNGIE presents as a gastrointestinal pseudo-obstruction, and may lead to neuropathy.
Illustrative mitochondrial diseases and myopathies include Myoclonic Epilepsy with Ragged Red Fibers (MERRF). MERRF is a progressive myoclonic epilepsy that is believed herein to be caused at least in part by mitochondrial dysfunction. MERRF is associated with ragged red fibers, clumps of diseased mitochondria that accumulate in the subsarcolemmal region of the muscle fiber. The “ragged red fibers” are observed when muscle is stained with modified Gömöri trichrome stain. MERRF reportedly leads to short stature, hearing loss, lactic acidosis, and/or exercise intolerance.
Illustrative mitochondrial diseases and myopathies include Mitochondrial myopathy, encephalomyopathy, lactic acidosis, stroke-like symptoms (MELAS).
Mitochondrial diseases and myopathies that may be treated using the compositions and methods described herein include those diseases that are characterized mitochondrial dysfunction, and may be accompanied by high levels of oxidative stress. The diseases themselves may be genetic, arise from a primary mutation that causes a mitochondrial dysfunction, and/or which causes high oxidative stress. Mitochondrial diseases and myopathies that may be treated using the compositions and methods described herein if left untreated may cause tissue damage and/or further genetic damage, the latter arising from additional mutations and protein damage, leading to a cascade of problems.
Friedreich's ataxia (FRDA) is the most common of the inherited ataxias, and affects 1 in 50,000 people in general, and approximately 1.5 per 100,000 per year among Europeans and North Americans of European descent. Friedreich ataxia is a progressive disorder with significant morbidity. Loss of ambulation typically occurs 15 years after disease onset. More than 95% of surviving patients are wheelchair bound by age 45 years. The average age of death is reportedly 37.7 years (range, 21-69) (see, Harding et al. J Med Genet. August 1981; 18(4):285-7). FRDA is an autosomal recessively inherited progressive neurodegenerative disease that is characterized by progressive neurodegeneration, diabetes and life-threatening hypertrophic cardiomyopathy. Clinically, FRDA is characterized by multiple symptoms including progressive gait and limb ataxia, dysarthria, diabetes mellitus and hypertrophic cardiomyopathy (Sturm et al., E. J. Clin. Invest. 2005; 35:711-717).
Friedreich's ataxia is reportedly caused by a GAA-trinucleotide repeat expansion within intron 1 of the FXN gene (Campuzano et al., Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion Science 271:1423-1427 (1996)), which induces FXN gene silencing and hence reduced expression of the essential mitochondrial protein frataxin (Campuzano et al., Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes Hum Mol Genet 6:1771-1780 (1997)). The frataxin gene is located on chromosome locus 9ql3. Without being bound by theory, due to the mitochondrial localization of frataxin, the neurological and cardiological degenerations observed in FRDA are believed herein to be the result of a mitochondrial defect. Although the exact physiological function of frataxin is unknown, without being bound by theory, it is believed herein that frataxin may be involved in mitochondrial iron homeostasis and/or assembly of iron-sulfur (FeS) proteins and heme synthesis. In particular, frataxin insufficiency reportedly leads to iron-sulfur cluster protein deficits, oxidative stress, mitochondrial iron accumulation and resultant cell death, with the primary site of pathology being in the large sensory neurons of the dorsal root ganglia (DRG) and the dentate nucleus of the cerebellum (Koeppen, Friedreich's ataxia: pathology, pathogenesis, and molecular genetics J Neurol Sci 303, 1-12 (2011)). Intramitochondrial iron accumulation has also been reported to possibly initiate the production of hydroxyl radicals, leading to inactivation of FeS enzymes, lipid peroxidation and damage to nucleic acids, and proteins. In addition, it has been reported that the outcome is progressive spinocerebellar neurodegeneration, diabetes and cardiomyopathy, with death commonly in early adulthood (Pandolfo, Friedreich ataxia: the clinical picture J Neurol 256 Suppl 1, 3-8 (2009)).
Despite remarkable progress in delineating the biochemical and genetic basis of mitochondrial disorders over the past 20 years, progress in establishing effective treatment has generally been limited. Many potential interventions have been proposed, most of which have not been demonstrated objectively to be beneficial (see, for example, DiMauro, Biochimica et Biophysica Acta 179:1159-1167 (2009))
Accordingly, compounds, compositions, and methods are needed for treating mitochondrial diseases, such as FRDA, LHON, DAD, Leigh's disease, NARP, MNGIE, MERRF, MELAS, and the like. It is believed herein that compounds that also exhibit antioxidant like behavior but which may be more than general antioxidants, or general oxidant scavengers, are useful in treating such mitochondrial diseases.
It has been discovered that tetracyclic pyrazinoindoles, and in particular, hydrogenated tetracyclic pyrazinoindoles, and pharmaceutically acceptable salts thereof, are useful in treating patients suffering from or in need of relief from FRDA, LHON, DAD, Leigh's disease, NARP, MNGIE, MERRF, MELAS, and like mitochondrial diseases. Without being bound by theory, it is believed herein that the compounds described herein protect, or directly protect, neuronal cells from the oxidative stress that accompanies FRDA, LHON, DAD, Leigh's disease, NARP, MNGIE, MERRF, MELAS, and like mitochondrial diseases. The use of tetracyclic pyrazinoindoles, or pharmaceutically acceptable salts thereof, in treating such mitochondrial diseases has heretofore been unknown.
In one illustrative embodiment of the invention described herein, methods are described for treating FRDA, LHON, DAD, Leigh's disease, NARP, MNGIE, MERRF, MELAS, and like mitochondrial diseases. In one aspect, the methods described herein include the step of administering a therapeutically effective amount of one or more tetracyclic pyrazinoindoles and/or pharmaceutically acceptable salts thereof to a patient suffering from, or in need of relief from one or more forms of FRDA, LHON, DAD, Leigh's disease, NARP, MNGIE, MERRF, MELAS, and like mitochondrial diseases. As used herein, FRDA, LHON, DAD, Leigh's disease, NARP, MNGIE, MERRF, MELAS, and like mitochondrial diseases include borderline forms of each of the foregoing. Borderline forms of such diseases include early forms of the diseases treatable herein, where diagnosis on the basis of symptoms may be difficult.
Illustrative compositions for use in the methods described herein include a therapeutically effective amount of one or more tetracyclic pyrazinoindoles and/or pharmaceutically acceptable salts thereof.
In another illustrative embodiment, the methods described herein include the step of co-administering a therapeutically effective amount of one or more tetracyclic pyrazinoindoles and/or pharmaceutically acceptable salts thereof, and a therapeutically effective amount of one or more other pharmaceutically effective agents. Illustrative other pharmaceutically effective agents include, but are not limited to, coenzyme Q10, and analogs and derivatives thereof, such as antioxidants, including idebenone, EPI-A0001, pioglitazone, ubiquinone, ubidecarenone, coenzyme Q, and the like, and/or pharmaceutically acceptable salts thereof, iron chelators, such as deferiprone, and the like, frataxin-increasing compounds, such as erythropoietin (EPO), and the like, histone deacetylase (HDAC) inhibitors, dimebolins, such as dimebon, and/or pharmaceutically acceptable salts thereof, certain vitamins, such as vitamin C, vitamin E, thiamine, and/or riboflavin, and/or pharmaceutically acceptable salts thereof, creatine, carnitine, and analogs and derivatives thereof, such as acetylcarnitine, acetyluridine, trolox, curcumin, alpha lipoic acid, dichloroacetate, pyruvate, and/or pharmaceutically acceptable salts of any of the foregoing.
In another embodiment, illustrative compositions include a therapeutically effective amount of one or more tetracyclic pyrazinoindoles and/or pharmaceutically acceptable salts thereof, and a therapeutically effective amount of another such pharmaceutically effective agent, such idebenone and/or pharmaceutically acceptable salts thereof. In another embodiment, the compositions include a therapeutically effective amount of one or more tetracyclic pyrazinoindoles and/or pharmaceutically acceptable salts thereof, and a therapeutically effective amount of trolox. In another embodiment, the compositions include a therapeutically effective amount of one or more tetracyclic pyrazinoindoles and/or pharmaceutically acceptable salts thereof, and a therapeutically effective amount of alpha-lipoic acid. In another embodiment, the compositions include a therapeutically effective amount of one or more tetracyclic pyrazinoindoles and/or pharmaceutically acceptable salts thereof, and a therapeutically effective amount of acetylcarnitine. It is to be understood that in each of the foregoing compositions, all combinations of compounds described herein may be included in the compositions, such as but not limited to a therapeutically effective amount of one or more tetracyclic pyrazinoindoles and/or pharmaceutically acceptable salts thereof, and a therapeutically effective amount of idebenone and/or pharmaceutically acceptable salts thereof, and a therapeutically effective amount of trolox to a patient.
In another illustrative embodiment, kits or packages are described herein. Illustrative kits and packages include instructions and preparations, where the co-administered compounds are placed in a format following the dosing protocol instructions, as described herein. For example, an illustrative package may include a grid pattern, wherein each section includes a dual or triple bubble pack for the one or more tetracyclic pyrazinoindole dosages, and illustratively one or more of the dimebolin dosage, idebenone dosage, trolox dosage, vitamin E dosage, the vitamin C dosage, and/or the CoQ10 dosage, and/or the acetylcarnitine dosage, and/or the carnitine dosage, and/or the acetyluridine dosage, and/or the curcumin dosage, and/or the dichloroacetate dosage, and/or the Pyruvate dosage, and/or the thiamine dosage, and/or the riboflavin dosage, and/or the Creatine dosage. It is appreciated that other configurations that include other combinations of one or more of the dimebolin dosage, CoQ10 dosage, idebenone dosage, the trolox dosage, the vitamin E dosage, the vitamin C dosage, the carnitine dosage, the acetylcarnitine dosage, the acetyluridine dosage, the curcumin dosage, the dichloroacetate dosage, the pyruvate dosage, the thiamine dosage, the riboflavin dosage, and/or the creatine dosage are described herein.